LARONIB 25 MG (LAROTRECTINIB)

LARONIB 25 MG (LAROTRECTINIB)

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Description

Laronib
Larotrectinib
25 mg & 100 mg

COMPOSITION
LARONIB 25 capsules: Each capsule contains Larotrectinib Sulfate INN equivalent to Larotrectinib 25 mg.

LARONIB 100 capsules: Each capsule contains Larotrectinib Sulfate INN equivalent to Larotrectinib 100 mg.

INDICATIONS AND USAGE
Solid Tumors

WARNING AND PRECAUTIONS

Neurotoxicity
Among the 176 patients who received Larotrectinib, neurologic adverse reactions of any grade occurred in 53% of patients, including Grade 3 and Grade 4 neurologic adverse reactions in 6% and 0.6% of patients, respectively. The majority
of neurologic adverse reactions occurred within the first three months of treatment (range: 1 day to years). Grade 3 neurologic adverse reactions included delirium (2%), dysarthria

USE IN SPECIFIC POPULATION

Pregnancy
Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of action, Larotrectinib can cause
embryo-letal harm when administered to a pregnant woman. There H
are no available data on Larotrectinib use in pregnant women.

Lactation

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Larotrectinib is indicated for the treatment of adult and pediatric
patients with solid tumors that:

Have a Neurotrophic Receptor Tyrosine Kinase (NTR ) gene fusion without a known acquired resistance mutation.

Are metastatic or where surgical resection is likely to result in severe morbidity, and

Have no satisfactory alternative treatments or that have progressed following treatment.

DOSAGE AND ADMINISTRATION
Adult and Pediatric Patients with Body Surface Area of at least 1.0 Meter-Squared.
The recommended dosage of Larotrectinib is 100 mg orally twice daily, with or without food, until disease progression or until unacceptable toxicity.

Pediatric Patients with Body Surface Area Less Than 1.0 Meter- Squared.
The recommended dosage of Larotrectinib is 100 mg/m’ orally twice daily, with or without food, until disease progression or until unacceptable toxicity.

Dosage Modifications for Adverse Reactions For Grade 3 or 4 adverse reactions:
Withhold Larotrectinib until adverse reaction resolves or improves to baseline or Grade 1. Resume at the next dosage modification if resolution occurs within 4 weeks.

Permanently discontinue Larotrectinib if an adverse reaction does not resolve within 4 weeks.

The recommended dosage modifications for Larotrectinib for adverse reactions are provided in Table 1.

Table 1. Recommended dosage modifications for Larotrectinib for adverse reactions

Dosage Modification Adult and Pediatric Patients with Body Surface Area of at Least 1.0 m! Pediatric Patients with Body sulace Area Less
Than 1.0 m°
First 75 mg orally twice daily 75 mg/m’ orally twice daily
Second 50 mg orally twice daily 50 mg/m’ orally twice daily
Third 100 mg orally once daily 25 mg/m’ orally twice daily

Permanently discontinue Larotrectinib in patients who are unable to tolerate Larotrectinib after three dose modifications.

Dosage Modifications for Coadministration with Strong CYP3A4 lnhibitors
Avoid coadministration of strong CYP3A4 inhibitors with Larotrectinib. If coadministration of a strong CYP3A4 inhibitor cannot be avoided, reduce the Larotrectinib dose by 50%. After the inhibitor has been discontinued for 3 to 5 elimination half-lives, resume the Larotrectinib dose taken prior to initiating the CYP3A4 inhibitor.

Dosage Modifications for Coadministration with Strong CYP3A4 Inducers
Avoid coadministration of strong CYP3A4 inducers with Larotrectinib. If coadministration of a strong CYP3A4 inducer cannot be avoided, double the Larotrectinib dose. After the inducer has been discontinued for 3 to 5 elimination half-lives, resume the Larotrectinib dose taken prior to initiating the CYP3A4 inducer.

Dosage Modifications for Patients with Hepatic Impairment Reduce the starting dose of Larotrectinib by 50% in patients with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic
(1%), dizziness gait (1%), and paresthesia
(1%). Grade 4 encephalopathy (0.6%) occurred in a single patient. Neurologic adverse reactions leading to dose modifica- tion dizziness gait disturbance delirium (1%), memory impairment (1%), and tremor

Advise patients and caretakers of these risks with Larotrectinib. Advise patients not to drive or operate hazardous machinery if they are experiencing neurologic adverse reactions. Withhold or permanently discontinue Larotrectinib based on the If
modify the Larotrectinib dosage when resumed.

Hepatotoxicity
Among the 176 patients who Larotrectinib, transaminases of any grade occurred in 45%, including Grade 3 increased AST or ALT in 6% of patients. One patient (0.6%) experienced Grade 4 increased ALT. The median time to onset of increased AST was 2 months (range: 1 month to 2.6 years). The median time to onset of increased ALT was 2 months (range: 1 month to 1.1 years). Increased AST and ALT leading to dose modifications occurred in 4% and 6% of patients, respectively. Increased AST or ALT led to permanent discontinuation in 2% of patients.

Monitor liver tests, including ALT and AST, every 2 weeks during the first month of treatment, then monthly and as clinically indicated. Withhold or permanently discontinue Larotrectinib based on the If withheld, modify the Larotrectinib dosage when resumed.

Embryo-Fetal Toxicity
Based on literature reports in human subjects with congenital mutations leading to changes in TRK signaling, findings from animal studies, and its mechanism of Larotrectinib can cause letal harm when administered to a pregnant woman. Larotrectinib resulted in rats and rabbits at maternal exposures that were approximately 11- and respectively, those observed at the clinical dose of 100 mg twice daily. Advise women of the potential risk to a Advise females of reproductive potential to use an effective method of contraception during treatment and for 1 week after the final dose of Larotrectinib.

SIDE EFFECTS
Neurotoxicity: [see Warnings and Precautions] Hepatotoxicity: [see Warnings and Precautions]
DRUG INTERACTIONS
Efiects of Other Drugs on Larotrectinib Strong CYP3A4 lnhibitors
Coadministration of Larotrectinib with a strong CYP3A4 inhibitor may increase Larotrectinib plasma concentrations, which may result in a higher incidence of adverse reactions. Avoid co administration of Larotrectinib with strong CYP3A4 inhibitors, including grapefruit or grapefruit juice. If coadministration of strong CYP3A4 inhibitors cannot be avoided, modify Larotrec- tinib dose as recommended.

Strong CYP3A4 lnducers
Coadministration of Larotrectinib with a strong GYP3A4 inducer may decrease Larotrectinib plasma concentrations, which may decrease the efficacy of Larotrectinib. Avoid coadministration of Larotrectinib with strong CYP3A4 inducers, including St. John’s wort. If coadministration of strong CYP3A4 inducers cannot be avoided, modify Larotrectinib dose as recommended.

Eflects of Larotrectinib on Other Drugs Sensitive CYP3A4 Substrates
Coadministration of Larotrectinib with sensitive CYP3A4 substrates may increase their plasma concentrations, which may increase the incidence or severity of adverse reactions. Avoid co
There is no data on the presence of Larotrectinib or its metabo-
lites in human milk and no data on its effects on the breastfed child or on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with Larotrectinib and for 1 week after the final dose.

Females and Males of Reproductive Potencial Pregnancy Testing
Verify pregnancy status in females of reproductive potential prior to initiating Larotrectinib.

Contraception
Larotrectinib can cause embryo-letal harm when administered to a pregnant woman.

Females
Advise female patients of reproductive potential to use effective contraception during treatment with Larotrectinib and for at least 1 week after the final dose.

Males
Advise males with female partners of reproductive potential to use effective contraception during treatment with Larotrectinib and for 1 week after the final dose.

Pediatric Use
Due to the small number of pediatric and adult patients, the single arm design of clinical studies of Larotrectinib, and confounding factors such as differences in susceptibility to infections between pediatric and adult patients, it is not possible to determine whether differences in the incidence of adverse reactions to Larotrectinib are related to patient age or other factors. Adverse reactions and laboratory abnormalities of Grade 3 or 4 severity occurring more frequently (at least a 5% increase in per-patient incidence) in pediatric patients compared to adult patients were increased weight (11% vs. 2%) and neutropenia (20% vs. 2%). One of the 44 pediatric patients discontinued Larotrectinib due to an adverse reaction (Grade 3 increased ALT).

The pharmacokinetics of Larotrectinib in the pediatric population were similar to those seen in adults.

Geriatric Use
Of 176 patients in the overall safety population who received Larotrectinib, 22% of patients were 65 years of age and 5% of patients were ú 75 years of age. Clinical studies of Larotrectinib did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjecta.

Hepatic Impairment
No dose adjustment is recommended for patients with mild hepatic impairment (Child-Pugh A). Larotrectinib clearance was reduced in subjecta with moderate (Child-Pugh B) to severe (Child-Pugh C) hepatic impairment. Reduce Larotrectinib dose as recommended.

Renal Impairment
No dose adjustment is recommended for patients with renal impairment of any severity.

OVERDOSE
No information available.

DESCRIPTION
Larotrectinib is a kinase inhibitor. The molecular formula for Larotrectinib sulfate is Cz‹Hz•FzNcOcS and the molecular weight is 526.51 g/mol for the sulfate salt and 428.44 g/moI for the free base. The chemical name is (3S)-N-(5-[(2R)-2-(2,5-difluoro- phenyl)-1-pyrrolidinyI] pyrazolo [1,5-a] pyrimidin-3-yl)-3-hy- droxy-1-pyrroIidinecarboxamide sulfate. Larotrectinib sulfate has the following chemical structure:
Larotrectinib sulfate is an off-white to pinkish yellow solid that is
not hygroscopic. The aqueous solubility of larotrectinib at 37°C is pH dependent (very soluble at pH 1.0 and freely soluble at pH 6.8, according to USP descriptive terms of solubility).

CLINICAL PHARMACOLOGY
Mechanism of Action
Larotrectinib is an inhibitor of the tropomyosin receptor kinases (TRK), TRKA, TRKB, and TRKC. In a broad panel of purified enzyme assays, Larotrectinib inhibited TRKA, TRKB, and TRKC with ICso values between 5-11 nM. One other kinase TNK2 was inhibited at approximately 100-foId higher concentration. TRKA, B, and C are encoded by the genes NTRK1, NTRK2, and NTRK3. Chromosomal rearrangements involving in-frame fusions of these genes with various partners can result in constitutively-activated chimeric TRK fusion proteins that can act as an oncogenic driver, promoting cell proliferation and survival in tumor cell lines.

In in vitro and in viva tumor models, Larotrectinib demonstrated anti-tumor activity in cells with constitutive activation of TRK proteins resulting from gene fusions, deletion of a protein regulatory domain, or in cells with TRK protein overexpression. Larotrectinib had minimal activity in cell lines with point mutations in the TRKA kinase domain, including the clinically identified acquired resistance mutation, G595R. Point mutations in the TRKC kinase domain with clinically identified acquired resistance to larotrectinib include G623R, G696A, and F617L.

NON CLINICAL TOXICOLOGY
Carcinogenesis, Mutagenesis, Impairment of Fertility Carcinogenicity studies have not been conducted with Larotrectinib. Larotrectinib was not mutagenic in the in vitro bacterial reverse mutation (Ames) assays, with or without metabolic activation, or in the in vitro mammalian mutagenesis assays, with or without metabolic activation. In vivo, larotrectinib was negative in the mouse micronucleus test.

Fertility studies with Larotrectinib have not been conducted. In a 3-month repeat-dose toxicity study in the rat, Larotrectinib had no effects on spermatogenesis at 75 mg/kg/day (approximately 7 times the human exposure at the 100 mg twice daily dose). Additionally, Larotrectinib had no histological effects on the male reproductive tract in rats or monkeys at doses resulting in exposures up to 10 times the human exposure (AUCo-z•r ) at the 100 mg twice daily clinical dose.

In a 1-month repeat-dose study in the rat, decreased uterine weight and uterine atrophy were seen at 200 mg/kg/day [approx- imately 45 times the human exposure (AUC) at the 100 mg twice daily dose]. Fewer corpora lutea and increased incidence of anestrus were also noted at doses 60 mg/kg/day (approxi- mately 10 times the human exposure at the 100 mg twice daily dose). Decreased fertility occurred in a juvenile animal study. There were no findings in female reproductive organs in repeat-dose studies in monkeys at exposures up to 22 times the human exposure at the 100 mg twice daily dose.

PHARMACEUTICAL INFORMATION
Storage Conditions
Do not store above 25°C. Do not remove desiccant. Dispense in original container.
Keep LARONIB out of reach and sight of the children. How supplied
LARONIB 25 capsule: Each HDPE container contains 30
capsules each of which contains Larotrectinib 25 mg.

LARONIB 100 capsule: Each HDPE container contains 30 capsules each of which contains Larotrectinib 100 mg.

impairment.

CONTRANDlCATlON
None
administration of Larotrectinib with sensitive CYP3A4 substrates.
If coadministration of these sensitive CYP3A4 substrates cannot be avoided, monitor patients for increased adverse reactions of these drugs.

Manufactured By
Everest Pharmaceuticals Ltd.

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